The present invention relates to tumor-associated peptides that are capable of binding to a molecule of the human class I major histocompatibility complex (MHC). Such peptides are, for example, used in the immunotherapy of tumor diseases.
The recognition of tumor-associated antigens (TAA) by immune system components plays a major role in the elimination of tumor cells by the immune system. This mechanism is based on the prerequisite that there are qualitative or quantitative differences between tumor cells and normal cells. In order to achieve an anti-tumor response, the tumor cells have to express antigens that are targets of an immune response sufficient for elimination of the tumor.
Particularly CD8-expressing cytotoxic T lymphocytes (in the following termed CTL) participate in tumor rejection. In order to elicit such an immune reaction by cytotoxic T cells, foreign proteins/peptides must be presented to the T cells. T cells recognize antigens as peptide fragments only if those are presented on cell surfaces by MHC molecules. These MHC (“major histocompatibility complex”) molecules are peptide receptors that normally bind peptides within the cell in order to transport them to the cell surface. This peptide/MHC molecule complex can be recognized by T cells. Human MHC molecules are termed human leukocyte antigens (HLA).
There are two classes of MHC molecules: MHC class I molecules, present on most nucleated cells, present peptides that are generated by proteolytic degradation of endogenous proteins. MHC class II molecules are only found on professional antigen presenting cells (APC), and present peptides of exogenous proteins that are engulfed and processed by APC during endocytosis. Complexes formed between peptide and MHC class I are recognized by CD8-positive cytotoxic T cells, complexes formed between peptide and MHC class II are recognized by CD4 T helper cells.
In order for a peptide to elicit a cellular immune response, it needs to bind to an MHC molecule. This process depends on the allele of the MHC molecule and on the amino acid sequence of the peptide. Usually, MHC class I-binding peptides have a length of 8-10 residues, and their sequences contain two conserved residues (“anchors”) interacting with the corresponding binding groove of the MHC molecule.
In order for the immune system to be able to elicit an effective CTL response against tumor-derived peptides, such peptides not only have to be able to bind to certain MHC class I molecules being expressed by tumor cells, they also have to be recognized by T cells bearing specific T cell receptors (TCR).
The main purpose for developing a tumor vaccine is the identification and characterization of tumor-associated antigens being recognized by CD8+CTL.
The antigens, or their epitopes, that are recognized by the tumor-specific cytotoxic T lymphocytes can be molecules from all protein classes, such as enzymes, receptors, transcription factors, etc. Another important class of tumor-associated antigens are tissue-specific structures such as CT (“cancer testis”) antigens that are expressed in various types of tumors and in healthy testicular tissue. For the proteins to be recognized as tumor-specific antigens by cytotoxic T lymphocytes, and to be therefore used in a therapy, certain conditions must be met: The antigen should mainly be expressed by tumor cells and not or only in smaller amounts by normal cells in contrast to tumors. Furthermore, it is desirable that the respective antigen is present in high concentration not only in one type of tumor but in other tumor types as well. The presence of epitopes in the amino acid sequence of the antigen is also absolutely mandatory since such peptides that are derived from a tumor-associated antigen (“immunogenic peptides”), should lead to a T cell response, either in vitro or in vivo.
Therefore, TAAs are a starting point for the development of a tumor vaccine. The methods for identifying and characterizing the TAAs are based on the use of CTL that have already been induced in the patients, or they are based on the generation of differential transcription profiles between tumors and normal tissues.
However, the identification of genes overexpressed in tumor tissues or human tumor cell lines, or selectively expressed in such tissues or cell lines, does not provide precise information as to the use of the antigens being transcribed from these genes in the immune therapy. This is because only individual epitopes of these antigens are suitable for such an application since only the antigen epitopes—not the entire antigen—elicit a T cell response through MHC presentation. It is therefore important to select only those peptides from overexpressed or selectively expressed proteins that are presented in connection with MHC molecules, so targets for the specific recognition of primary cells or of tumor cell lines established from primary tumor tissue cells, by cytotoxic T lymphocytes could be obtained.